OBJECTIVE: To determine the effect of PNU-91325, an insulin sensitizer from the Thiazolidinedione chemical class, on insulin and glucose metabolism in mildly to moderately obese rhesus monkeys. RESULTS Six adult male rhesus monkeys (body weight > 13 kg) were used for the experiment. The monkeys were studied during the following successive two week periods Placebo 1, Low Dose (0.3 mg/kg/day), Intermediate dose (3 mg/kg/day), High dose 1 (30 mg/kg/day), High dose 2 (30 mg/kg/day), and Placebo 2. Each treatment period was followed by a two week washout period, except for High Dose 1 which was immediately followed by High Dose 2. During all phases of the experiment, food intake was measured daily and body weight was measured weekly. Meal tolerance tests, frequently sampled glucose tolerance tests with minimal model analysis, blood pressure, heart rate, and plasma triglyeride and cholesterol subfractions were measured at the end of each assessment period. Body weight was not significantly (p > 0.05) changed by drug treatment. Systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate were all decreased (p < 0.05) following the Intermediate dose phase when compared to the Placebo phases. These blood pressure and heart changes, however, disappeared at the High dose treatments. No treatment related differences in insulin, glucose, or lactate were noticed during the meal tolerance test. Plasma triglyerides and HDL triglycerides, were consistently elevated (p < 0.05) during the meal tolerance test in the Placebo 2 phase when compared to the drug treatment phases. Basal insulin, basal glucose, second phase insulin response to glucose, insulin response to tolbutamide, glucose disappearance rate, insulin sensitivity, and glucose effectiveness were not significantly (p > 0.05) altered by drug treatment. PNU-91325 either had no effect or transient effects on measures of blood pressure or insulin and glucose parameters. Plasma triglycerides were dramatically increased following cessation of drug treatment, however, additional research will be needed to determine if PNU-91325 plays any role in regulating plasma triglyeride levels. FUTURE DIRECTIONS We are continuing to test novel insulin sensitizing agents for efficacy in treating non-insulin dependent diabetes . KEY WORDS insulin, glucose, triglycerides, diabetes